Review of evidence implicating the plasminogen activator system in blood-brain barrier dysfunction associated with Alzheimer's disease

Abstract

Elucidating the pathogenic mechanisms of Alzheimer's disease (AD) to identify therapeutic targets has been the focus of many decades of research. While deposition of extracellular amyloid-beta plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated tau have historically been the two characteristic hallmarks of AD pathology, therapeutic strategies targeting these proteinopathies have not been successful in the clinics. Neuroinflammation has been gaining more attention as a therapeutic target because increasing evidence implicates neuroinflammation as a key factor in the early onset of AD disease progression. The peripheral immune response has emerged as an important contributor to the chronic neuroinflammation associated with AD pathophysiology. In this context, the plasminogen activator system (PAS), also referred to as the vasculature's fibrinolytic system, is emerging as a potential factor in AD pathogenesis. Evolving evidence suggests that the PAS plays a role in linking chronic peripheral inflammatory conditions to neuroinflammation in the brain. While the PAS is better known for its peripheral functions, components of the PAS are expressed in the brain and have been demonstrated to alter neuroinflammation and blood-brain barrier (BBB) permeation. Here, we review plasmin-dependent and -independent mechanisms by which the PAS modulates the BBB in AD pathogenesis and discuss therapeutic implications of these observations.

Keywords: Bradykinin; matrix metalloproteinase; neuroinflammation; neurovascular unit; plasmin; tissue-type plasminogen activator.

Figure 1.

Schematic diagram of the molecular mechanisms of the plasminogen activator system. PAI-1: Plasminogen activator inhibitor-1; NSP: neuroserpin; uPA: urokinase-type plasminogen activator; tPA: tissue-type plasminogen activator; PLG: plasminogen; PLM: plasmin. Created with BioRender.com.

Figure 2.

Cross-section of the neurovascular unit (NVU) in a normal brain vs. an Alzheimer’s disease (AD) brain. The blood-brain barrier (BBB) consists of endothelial cells joined by tight junctions, basement membrane, mural cells (i.e., pericytes and vascular smooth muscle cells), enclosed by astrocytic endfeet. Neurons and microglia closely associate with the BBB. In the AD brain, the NVU undergoes morphological and structural changes due to AD pathology. Amyloid-beta plaques complexed to fibrin result in neuroinflammation and BBB disruption, including activated microglia, swollen astrocytic endfeet, and compromised tight junctions. Created with BioRender.com.

Figure 3.

Mechanisms by which tPA may disrupt the blood-brain barrier. (1) tissue-type plasminogen activator(tPA) released from neurons cleaves lipoprotein receptor-related protein-1 (LRP-1) to activate an NF-κB signaling cascade resulting in the production of MMP-9. tPA and LRP-1 can bind amyloid beta, which facilitates Aβ endocytosis across the blood-brain barrier (BBB). (2) Neuronal tPA degrades platelet-derived growth factor-CC (PDGF-CC) to release the active ligand for PDGF receptor-α (PDGFR-α) on astrocytic endfeet, causing them to retract from endothelial cells. (3) Plasma tPA activates plasmin to directly produce bradykinin that activates bradykinin 2 receptor (B2R) receptor on endothelial cells. (4) Plasma tPA cleaves plasminogen to generate plasmin that indirectly upregulates bradykinin expression through plasma kallikrein (PKal). Created with BioRender.com.